The overall aim of this proposal is to study the prospective association between serum levels of PFCs and the risk of developing coronary heart disease (CHD), stroke, cardiovascular disease (CVD), subclinical measures of atherosclerosis and hypertensive left ventricular changes among the participants of the of the Multi-ethnic Study of Atherosclerosis (MESA), a large, multiethnic, population-based, longitudinal cohort study with participants representing both men and women and the various racial/ethnic groups in the US, including whites, blacks, Hispanics, and Asian Americans and with up to 10 years of follow-up data. We will also evaluate gender and racial/ethnic differences in PFC exposure among Americans in this contemporary general population sample and examine if the association between PFCs and CVD vary by gender, or race/ethnicity. Ours is an ancillary study that builds upon the existing strengths and resources of the NIH-funded, parent MESA cohort study to address our multiple study aims in an efficient and cost-effective manner. In the MESA, we already have data on 1) the main study outcomes, including incident CHD, stroke, and CVD validated following standard criteria and procedures adapted from other successful studies such as the NHLBI-funded ARIC study, subclinical measures of atherosclerosis including coronary artery calcium (CAC), abdominal aortic calcium (AAC), carotid intimal-medial thickness (CIMT), low ankle-brachial index (ABI), and hypertensive left ventricular parameters including left ventricular mass, volume and mass to volume (M/V) ratio 2) detailed questionnaire, physical examination, and laboratory data on potential confounding factors such as smoking, alcohol intake, body mass index (BMI), blood pressure, fasting glucose, serum lipids, high sensitivity C-reactive protein, and several other markers. In the current study, we propose a case-cohort study nested within the MESA cohort to newly measure serum levels of perfluorooctanoic acid (PFOS), perfluorooctane sulfonate (PFOA), perfluorohexane sulfonate (PFHxS), perfluorononanoic acid (PFNA), and 7 other commonly detected PFCs, including perfluoroheptanoic acid (PFHpA), perfluorodecanoic acid (PFDA), perfluoroundecanoic acid (PFUnA), perfluorododecanoic acid (PFDoA), perflurooctane sulfanomide (PFOSA), 2-(N-ethyl-perflurooctane sulfonamido) acetic acid (Et-PFOSA-AcOH), and 2-(N-methyl-perflurooctane sulfonamide) acetic acid (Me- PFOSA-AcOH), in the baseline serum of all incident CHD (n=523), and stroke (n=224), cases and a race- stratified cohort random sample of n=1000 participants (35% white, 28% black, 22% Hispanic and 12% Chinese). This study design will allow us to examine the longitudinal associations between baseline serum PFC levels and multiple outcomes using the same control group as well as to make valid cross-sectional comparisons (e.g. serum PFC levels by race-ethnicity). Our study is significant because it addresses a critical barrier in the field: the lack of longitudinal studies examining the relationship between PFC exposure and the risk of clinical and subclinical measures of CVD. PUBLIC HEALTH RELEVANCE: Perfluroalkyl chemicals (PFC) are detectable in the blood of >98% of US adults. We will study the association between blood PFCs and cardiovascular disease. If we find an association, it indirectly suggests that reducing PFCs may have a role in preventing these diseases.